Dimethylformamide → N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

HRID 1499626Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1499626
[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[F:20].[NH2:21][C:22]1[C:23]([N:31]2[CH2:36][C@H:35]([CH3:37])[C@@H:34]([O:38][Si](C(C)(C)C)(C)C)[C@H:33]([NH:46]C(=O)OC(C)(C)C)[CH2:32]2)=[C:24]2[CH2:30][CH2:29][O:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[NH2:46][C@H:33]1[C@H:34]([OH:38])[C@@H:35]([CH3:37])[CH2:36][N:31]([C:23]2[C:22]([NH:21][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C:3]4[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])[N:16]=3)=[O:19])=[CH:27][N:26]=[C:25]3[O:28][CH2:29][CH2:30][C:24]=23)[CH2:32]1

Komponenten

5

Edukt 4

HCID 6228DimethylformamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 592265336-(2,6-Difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acidHCID 86726732tert-Butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

Produkt 1

HCID 86726844N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamideAusbeute 32,2 %

Versuchsvorschrift

To a mixture of 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (176 mg, 0.372 mmol), tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (152 mg, 0.317 mmol), and HATU (374 mg, 0.983 mmol) in DMF (3.0 mL) DIPEA (238 mg, 1.84 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (54 mg, 32%). LCMS calc. for C26H27F3N5O4 (M+H)+: m/z=530.2. found 530.0. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.70 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t, J=8.8 Hz, 1H), 7.39-7.32 (m, 1H), 7.24-7.17 (m, 1H), 4.53-4.44 (m, 2H), 4.41 (d, J=3.8 Hz, 1H), 3.89 (s, 3H), 3.36 (t, J=8.5 Hz, 2H), 3.10-3.04 (m, 1H), 3.00-2.93 (m, 1H), 2.63 (t, J=10.8 Hz, 1H), 2.58-2.51 (m, 2H), 2.46-2.38 (m, 1H), 1.66 (br, 2H), 1.48-1.36 (m, 1H), 0.69 (d, J=6.5 Hz, 3H) ppm.

Aufarbeitung

  1. additionwas added
  2. concentrationconcentrated under reduced pressure
  3. additionTo the resulting residue, DCM (2.0 mL) was added
  4. stirringThe mixture was stirred at room temperature for 30 min.
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified
  7. washeluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.)

Quellen und Nachweise

ORD-Eintrag
ord-b9eff044a00e40c29264965dcb464160
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09200004B2

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